As our nation ages, the neurological diseases of later adulthood have become more prevalent. The number of Alzheimer's disease (AD) diagnoses has increased in the past decades, taking a large financial and emotional toll on our health care system. What makes some patients more susceptible to AD than others? Over twenty years ago, the ApoE4 allele was identified as a major genetic risk factor for late onset AD (1, 2). One of ApoE4's effects in the central nervous system (CNS) is to reduce the ability of neurons to respond to reelin signaling (3). Reelin is a neuromodulator that decreases with age and is especially reduced in Alzheimer's disease (4, 5). In vitro, reelin promotes synaptic plasticity, an mice injected with reelin intra- ventricularly have improved performance on learning and memory tasks (6, 7). Importantly, reelin protects in vitro against the toxicity induced by A oligomers, a toxic particle that builds up gradually in Alzheimer's disease (8-10). Additionally, a recent study demonstrated that Reelin overexpression in a mouse model of AD rescued cognitive defects and delayed amyloid plaque development (11). Genetic studies on the effect of reelin loss in mice have been hindered by the fact that reelin plays a large role in brain development (12). To circumvent the problem presented by this developmental issue, we have generated a conditional reelin knockout mouse in which reelin is expressed normally until the mice are injected with Tamoxifen. I will use this mouse to study the effect of reelin loss in aging related disease phenotypes. To determine the clinical relevance of reelin reduction in AD, it is important to study these conditional reelin knockout mice on a background of normal adult synaptic plasticity as well as Alzheimer's disease pathology. Initial results from my preliminary data and the literature suggest that reelin has a protective effect against A-induced neurodegeneration. The primary goals of this research are to 1) elucidate the role reelin has in normal adult synaptic function; 2) determine the role in vivo for reelin to combat A toxicity. These goals will be accomplished by a combination of behavioral studies of learning and memory, electrophysiological experiments on synaptic function, and biochemical and histological characterization. To study the protective role of reelin against AD, I will cross the conditional knockout mice with APPSwe mice, an Alzheimer's disease mouse model that expresses high levels of A.The data generated by this study can be used to propose new models of the role of reelin in adult neuronal function and AD and generate new therapeutic ideas to use alterations in reelin levels as a neuroprotective agent in neurological diseases of aging.